Devices and methods for controlling blood perfusion pressure along with regional mild hypothermia

ABSTRACT

Methods and devices for controlling blood perfusion pressure along with regional mild hypothermia. In at least one embodiment of a device for controlling blood perfusion pressure within a vessel of the present disclosure, the device comprises an elongated body having a lumen, a proximal end configured for placement in a first area having a first blood pressure, and a distal end configured for placement in a second area having a second blood pressure, a partial occluder positioned within the lumen of the elongated body between the proximal end and the distal end, the partial occluder configured so not to fully occlude a blood vessel and to equalize the first blood pressure at the first area with the second blood pressure at the second area, and a regional hypothermia system operably coupled thereto, the regional hypothermia system operable to reduce and/or regulate a temperature of a bodily fluid flowing therethrough.

PRIORITY

The present application is related to, claims the priority benefit of,and is a U.S. continuation patent application of, U.S. Nonprovisionalpatent application Ser. No. 13/965,548, filed Aug. 13, 2013, which (a)is related to, and claims the priority benefit of, U.S. ProvisionalPatent Application Ser. No. 61/682,345, filed Aug. 13, 2012, and (b) isrelated to, claims the priority benefit of, and is acontinuation-in-part of, U.S. patent application Ser. No. 13/562,602,filed Jul. 31, 2012 and issued as U.S. Pat. No. 9,132,010 on Sep. 15,2015, which is related to, claims the priority benefit of, and is acontinuation application of, U.S. patent application Ser. No.11/997,139, filed May 14, 2008 and issued as U.S. Pat. No. 8,231,646 onJul. 31, 2012, which is related to, claims the priority benefit of, andis a § 371 national stage application of, International PatentApplication Serial No. PCT/US2006/029223, filed Jul. 28, 2006, which isrelated to, and claims the priority benefit of, U.S. Provisional PatentApplication Ser. No. 60/703,422, filed Jul. 29, 2005. The contents ofeach of the aforementioned applications and patent are herebyincorporated by reference in their entirety into this disclosure.

BACKGROUND

The concept of myocardial salvage through coronary sinus interventiondates back to the nineteenth century. The objective has been to increasethe flow of oxygenated blood to the ischemic myocardium by perfusing thecoronary bed retrogradely from the coronary sinus; i.e., coronaryretroperfusion. To date, a number of retroperfusion methods have beendeveloped. Pressure-controlled intermittent coronary sinus occlusion(PICSO) has been used in conjunction with a balloon-tipped catheterpositioned just beyond the orifice of the coronary sinus with theproximal end connected to a pneumatic pump that automatically inflatesand deflates the balloon according to a preset cycle. Synchronizedretrograde perfusion, SRP and simplified retroperfusion are othertechniques that actively pump arterial and venous blood in the formerand the latter, respectively. The left ventricle-powered coronary sinusretroperfusion technique has focused on driving left ventricular bloodinto the coronary sinus through a surgically created left ventricle tocoronary sinus shunt.

Prior studies have shown the efficacy of venous retroperfusion. It hasbeen demonstrated that (1) coronary venous bypass-graft (CVBG) orpercutaneous in situ coronary venous arterialization (PICVA) permitsurvival in the presence of LAD arterial ligation as compared with theuniform non-viability of just LAD arterial ligation withoutretroperfusion; (2) retroperfusion is effective because it perfuses alllayers of the heart, including the subendocardium; and (3) considerablerecovery of regional myocardial function with low regional capillaryblood flows and low levels of retrograde arterial outflow provideevidence for possible oxygen delivery via the intramyocardial venousplexus.

The CVBG or PICVA procedure has a number of advantages over theconventional coronary artery bypass graft (CABG) procedure, including:(1) approximately 20% of revascularization candidates haveangiographically diffuse atherosclerotic changes with poor runoff orsmall coronary arteries which makes arterial bypass or percutaneouscoronary angioplasty (PTCA) unlikely to succeed. In those cases, CVBGmay be the procedure of choice. Furthermore, the runoff for the coronaryveins are significantly larger than those of arteries and hence thesurgical implementation is much easier as is the improved patency of thegraft. (2) The coronary venous system of the heart rarely undergoesatherosclerotic changes. This reduces the problem of restenosis that iscommonly evident with the CABG procedure and should reduce the need formultiple surgeries throughout the patient's lifespan. (3) The CVBG issurgically easier to implement than the CABG procedure and does notrequire cardiac arrest and the use of extracorporeal circulation. TheCVBG procedure can be implemented in the beating heart with the use of acardiac restrainer. This reduces the surgical risks and ensures quickerrecovery, which is particularly important in the elderly and theseverely ill patients.

To emphasize the importance of this field in terms of numbers, there areabout 1.4 million annual incidences of myocardial infarction in the U.S.and an equal number in Western Europe. Approximately 20% of thosepatients are not good candidates for bypass because of diffuse coronaryartery disease. Those patients have little treatment options other thanheart transplant. The number of heart transplants is meager, however, at2,000 in 2005. Many of those patients progress to heart failure wherethe cost of treatment of is very high ($40 billion annually in USrepresenting 5.4% of total health care cost). The prospect of a deviceto treat those patients is great in terms of lives saved as well ascosts reduction associated with heart failure.

Thus, a need exists in the art for an alternative to the conventionaltechniques of treating heart failure using retroperfusion such that thetechnique should be minimally invasive, easy to use and understand,simple to implement and effective in producing desired results.

BRIEF SUMMARY

The present disclosure relates generally to controlling blood pressure,including devices and methods for controlling blood pressure using aretrograde cannula.

The present disclosure provides devices and methods for assisting in theproper retroperfusion of various organs (e.g., brain, eye, etc.) but inparticular the heart. A general goal is to develop a coronary venousretroperfusion cannula that will provide perfusion of the coronary bedretrogradely through the coronary sinus with arterial blood generatedfrom a peripheral artery with no need for a pump. The cannula will beintroduced from the axillary or femoral vein under local anesthesia andthe proximal end, which consists of a graft, will be anastomosed to theaxillary or femoral artery, respectively. Furthermore, the cannula willinitially impose a significant pressure drop (approximately 50 mmHg) dueto inflation of a balloon or an obstruction (stenosis) made ofresorbable material, and hence will only transmit a fraction of thearterial pressure to the venous system. The intermediate pressure can beused to arterialize the venous system for 2 to 3 weeks and can then beraised to arterial pressure by release of the stenosis.

In the case of a resorbable material, as the material resorbs over aseveral week period, it will reduce the pressure drop and hence transmitmore of the arterial pressure to the venous system. This addresses amajor problem with coronary venous retroperfusion, which is the suddenincrease in pressure (venous to arterial) that results in vessel edemaand hemorrhage. Here, a novel cannula is presented which provides agradual increase in pressure to allow the venous system to arterialize.The gradual increase in pressure allows arterializations of the venoussystem, which prevent vessel rupture. Some of the advantages of thepresent disclosure include, but are not limited to: (1) design of acannula with a stenosis that will provide the desired initial pressuredrop and ensure undisturbed flow into the coronary venous system; (2)pre-arterialization of the venous system to prevent edema andhemorrhage, (3) elimination of the need for a pump as blood is deliveredfrom the patient's artery; (4) percutaneous delivery of the system withno need for open heart surgery; and (5) delivery of cannula in thebeating heart to eliminate cardiac arrest such as in bypass surgery.

Since the coronary veins do not develop arteriosclerosis, it isdesirable to use these vessels as conduits for revascularization. Morethan 60 years ago, Roberts et al. suggested the use of coronary veins asconduits to deliver oxygenated blood in a retrograde manner in animalstudies. Five years after this seminal study, Beck and colleaguesperformed the coronary retroperfusion procedure in humans. The methodwas abandoned, however, due to the high mortality rate from the edemaand hemorrhage that result due to the elevated pressure. Furthermore,graft clots and atherosclerotic changes occur in the venous vessels inresponse to the abrupt change in pressure, which lead to progressivevenous obliteration.

In order to remedy these difficulties, the present disclosure avoidsincreasing the pressure in the coronary vein from venous (10-20 mmHg) toarterial values (100-120 mmHg) in a single step. Instead, a cannula ispresented that regulates the pressure in the venous system over time toa more gradual increase in pressure. This procedure allows the venousvessels to arterialize and the vessel walls to thicken in order todecrease the stress and prevent rupture of the post capillary venules.Furthermore, the gradual increase in pressure will decrease the injuryresponse and subsequently reduce the atherosclerotic changes of thelarge epicardial veins.

In at least one exemplary embodiment of a device for controlling bloodperfusion pressure within a vessel of the present disclosure, the devicecomprises an elongated body having a lumen, a proximal end configuredfor placement in a first area having a first blood pressure, and adistal end configured for placement in a second area having a secondblood pressure, and a partial occluder positioned within the lumen ofthe elongated body between the proximal end and the distal end, thepartial occluder configured so not to fully occlude a blood vessel,wherein the partial occluder is configured to equalize the first bloodpressure at the first area with the second blood pressure at the secondarea. In another embodiment, at least one of the proximal end and thedistal end is/are configured for placement within a mammalian heart. Inyet another embodiment, the proximal end is configured for placementwithin an axillary artery or a femoral artery. In an additionalembodiment, the distal end is configured for placement within anaxillary vein or a femoral vein.

In at least one exemplary embodiment of a device for controlling bloodperfusion pressure within a vessel of the present disclosure, thepartial occluder comprises a resorbable stenosis, wherein the resorbablestenosis is configured to be resorbed over time when contacted by bloodflowing from the proximal end to the distal end of the elongated body.In an additional embodiment, the resorbable stenosis is furtherconfigured to gradually equalize the first blood pressure at the firstarea with the second blood pressure at the second area. In yet anadditional embodiment, the resorbable stenosis comprises a materialselected from the group consisting of polyols and magnesium alloy.

In at least one exemplary embodiment of a device for controlling bloodperfusion pressure within a vessel of the present disclosure, thepartial occluder comprises an occlusion balloon, wherein the occlusionballoon is configured for inflation to partially occlude the lumen whenin an inflated state and further configured for deflation or removalafter a period of time. In another embodiment, the occlusion balloon isfurther configured to gradually equalize the first blood pressure at thefirst area with the second blood pressure at the second area. In yetanother embodiment, the partial occluder is located closer to theproximal end than the distal end of the elongated body. In an additionalembodiment, the elongated body further comprises an anchoring balloonconfigured to anchor the elongated body within part of a circulatorysystem.

In at least one embodiment of a method for conditioning a blood vesselto operate under higher blood pressures of the present disclosure, themethod comprises introducing a distal end of an elongated tubular bodyinto a blood vessel to be conditioned, the blood vessel having a firstblood pressure therein and the elongated tubular body comprising aninterior having a stenosis, the stenosis configured so not to fullyocclude the blood vessel, introducing a proximal end of the elongatedtubular body into a second blood vessel such that blood flow is receivedwithin the interior of the elongated tubular body, the second bloodvessel comprising second blood pressure therein which is higher than thefirst blood pressure, and reducing the size of the stenosis over timesuch that the first blood pressure at the distal end of the elongatedbody is approximately the same as the second blood pressure at theproximal end. In another embodiment, the elongated tubular bodyintroduced into the blood vessel and the second blood vessel furthercomprises an anchoring balloon configured to anchor the elongatedtubular body within part of a circulatory system, and wherein the methodfurther comprises the step of inflating the anchoring balloon to anchorthe elongated tubular body within the blood vessel or the second bloodvessel. In yet another embodiment, the stenosis comprises a balloonocclusion and the step of reducing the size of the stenosis over timecomprises deflating or removing the balloon occlusion positioned withinthe interior of the elongated tubular body. In an additional embodiment,the stenosis comprises a resorbable stenosis and the step of reducingthe size of the stenosis over time comprises deflating the gradualresorption of the stenosis within the interior of the elongated tubularbody.

In at least one embodiment of a cannula for creating retrograde flowwithin part of a circulatory system of the present disclosure, thecannula comprises an elongated body having a lumen, a proximal endconfigured for placement in a first area having a first blood pressure,a distal end configured for placement in a second area having a secondblood pressure, wherein the first blood pressure is higher than thesecond blood pressure, and a partial occluder positioned within thelumen of the elongated body between the proximal end and the distal endand closer to the proximal end than the distal end, the partial occluderselected from the group consisting of an occluder balloon and aresorbable stenosis, the partial occluder configured so not to fullyocclude a blood vessel, wherein the partial occluder is configured togradually equalize the first blood pressure at the first area with thesecond blood pressure at the second area. In another embodiment, theelongated body further comprises an anchoring balloon configured toanchor the elongated body within part of a circulatory system. In yetanother embodiment, the partial occluder comprises the resorbablestenosis, wherein the resorbable stenosis is configured to be resorbedover time when contacted by blood flowing from the proximal end to thedistal end of the elongated body. In an additional embodiment, thepartial occluder comprises the occlusion balloon, wherein the occlusionballoon is configured for inflation to partially occlude the lumen whenin an inflated state and further configured for deflation or removalafter a period of time. In yet an additional embodiment, the proximalend is configured for placement within an axillary artery or a femoralartery, and wherein the distal end is configured for placement within anaxillary vein or a femoral vein.

In various devices, methods, and/or cannulas of the present disclosure,the devices, cannulas, and/or systems comprising the same and/orcomponents of the same, further comprise a regional hypothermia systemof the present disclosure operably coupled thereto, the regionalhypothermia system operable to reduce and/or regulate the temperature ofa fluid flowing therethrough, such as blood, and/or operable to reduceand/or regulate the temperature of a vessel, a tissue, and/or an organat or near the blood. In other embodiments, the regional hypothermiasystem comprises a heat exchanger configured to reduce and/or regulatethe temperature of the fluid. In various embodiments, one or morecomponents of the regional hypothermia system uses a cooling product toreduce and/or regulate the temperature of the fluid. In any number ofembodiments, the devices and/or cannulas further comprise one or moretemperature sensors coupled thereto, the one or more temperature sensorsoperable to detect a temperature of the blood, the vessel, the tissue,and/or the organ. In various embodiments, the devices and/or cannulasfurther comprise a remote module in wired or wireless communication withthe one or more temperature sensors, the remote module operable to andconfigured to receive the detected temperature(s) and process the sameto regulate, reduce, and/or increase the temperature of the blood, thevessel, the tissue, and/or the organ by way of altering the operation ofthe regional hypothermia system.

In at least one embodiment of a kit of the present disclosure, the kitcomprises a regional hypothermia system of the present disclosure, and adevice, a cannula, and/or a system comprising the same and/or componentsof the same. In various embodiments, the kit is useful to treat acondition of a mammalian tissue and/or organ by way of reducing blood,other fluid, tissue, and/or organ temperature and/or regulating thetemperature of the same.

In at least one embodiment of a device for controlling blood perfusionpressure within a vessel (a perfusion device) of the present disclosure,the device comprises an elongated body having a lumen, a proximal endconfigured for placement in a first area having a first blood pressure,and a distal end configured for placement in a second area having asecond blood pressure, a partial occluder positioned within the lumen ofthe elongated body between the proximal end and the distal end, thepartial occluder configured so not to fully occlude a blood vessel andto equalize the first blood pressure at the first area with the secondblood pressure at the second area, and a regional hypothermia systemoperably coupled thereto, the regional hypothermia system operable toreduce and/or regulate a temperature of a bodily fluid flowingtherethrough. In another embodiment, the regional hypothermia system isfurther operable to reduce and/or regulate a temperature of a portion ofa mammalian body, the portion selected from the group consisting of avessel, a tissue, and an organ. In yet another embodiment, the regionalhypothermia system comprises a heat exchanger configured to reduceand/or regulate the temperature of the bodily fluid. In an additionalembodiment, one or more components of the regional hypothermia systemuses a cooling product to reduce and/or regulate the temperature of thebodily fluid.

In at least one embodiment of a device for controlling blood perfusionpressure within a vessel (a perfusion device) of the present disclosure,the device further comprises one or more temperature sensors coupled tothe device, the one or more temperature sensors operable to detect thetemperature of the bodily fluid. In an additional embodiment, theregional hypothermia system further comprises a remote module in wiredor wireless communication with the one or more temperature sensors, theremote module operable to and configured to receive the detectedtemperature(s) and process the same to regulate, reduce, and/or increasethe temperature of the bodily fluid by way of altering an operation ofthe regional hypothermia system. In yet an additional embodiment, thepartial occluder comprises a resorbable stenosis, wherein the resorbablestenosis is configured to be resorbed over time when contacted by bloodflowing from the proximal end to the distal end of the elongated body.In another embodiment, the partial occluder comprises an occlusionballoon, wherein the occlusion balloon is configured for inflation topartially occlude the lumen when in an inflated state and furtherconfigured for deflation or removal after a period of time. In yetanother embodiment, the elongated body further comprises an anchoringballoon configured to anchor the elongated body within part of acirculatory system.

In at least one embodiment of a method for conditioning a blood vesselto operate under higher blood pressures (a method) of the presentdisclosure, the method comprises the steps of introducing a distal endof an elongated tubular body into a blood vessel to be conditioned, theblood vessel having a first blood pressure therein and the elongatedtubular body comprising an interior having a stenosis, the stenosisconfigured so not to fully occlude the blood vessel, introducing aproximal end of the elongated tubular body into a second blood vesselsuch that blood flow is received within the interior of the elongatedtubular body, the second blood vessel comprising second blood pressuretherein which is higher than the first blood pressure, reducing and/orregulating a temperature of blood flowing through the elongated tubularbody using a regional hypothermia system operably coupled to theelongated tubular body, and reducing the size of the stenosis over timesuch that the first blood pressure at the distal end of the elongatedbody is approximately the same as the second blood pressure at theproximal end. In another embodiment, the elongated tubular bodyintroduced into the blood vessel and the second blood vessel furthercomprises an anchoring balloon configured to anchor the elongatedtubular body within part of a circulatory system, and wherein the methodfurther comprises the step of inflating the anchoring balloon to anchorthe elongated tubular body within the blood vessel or the second bloodvessel. In yet another embodiment, the stenosis comprises a balloonocclusion and the step of reducing the size of the stenosis over timecomprises deflating or removing the balloon occlusion positioned withinthe interior of the elongated tubular body. In an additional embodiment,the stenosis comprises a resorbable stenosis and the step of reducingthe size of the stenosis over time comprises deflating the gradualresorption of the stenosis within the interior of the elongated tubularbody. In yet an additional embodiment, the step of reducing and/orregulating a temperature of blood flowing through the elongated tubularbody is performed to treat a cardiac condition.

In at least one embodiment of a cannula for creating retrograde flowwithin part of a circulatory system (a cannula) of the presentdisclosure, the cannula comprises an elongated body having a lumen, aproximal end configured for placement in a first area having a firstblood pressure, a distal end configured for placement in a second areahaving a second blood pressure, wherein the first blood pressure ishigher than the second blood pressure, a partial occluder positionedwithin the lumen of the elongated body between the proximal end and thedistal end and closer to the proximal end than the distal end, thepartial occluder selected from the group consisting of an occluderballoon and a resorbable stenosis, the partial occluder configured sonot to fully occlude a blood vessel and to gradually equalize the firstblood pressure at the first area with the second blood pressure at thesecond area, and a regional hypothermia system operably coupled thereto,the regional hypothermia system operable to reduce and/or regulate atemperature of a bodily fluid flowing therethrough. In anotherembodiment, the regional hypothermia system is further operable toreduce and/or regulate a temperature of a portion of a mammalian body,the portion selected from the group consisting of a vessel, a tissue,and an organ. In yet another embodiment, the regional hypothermia systemcomprises a heat exchanger configured to reduce and/or regulate thetemperature of the bodily fluid. In an additional embodiment, thecannula further comprises one or more temperature sensors coupledthereto, the one or more temperature sensors operable to detect thetemperature of the bodily fluid.

In at least one embodiment of a cannula for creating retrograde flowwithin part of a circulatory system (a cannula) of the presentdisclosure, the elongated body further comprises an anchoring balloonconfigured to anchor the elongated body within part of a circulatorysystem. In an additional embodiment, the partial occluder comprises theresorbable stenosis, wherein the resorbable stenosis is configured to beresorbed over time when contacted by blood flowing from the proximal endto the distal end of the elongated body. In yet an additionalembodiment, the partial occluder comprises the occlusion balloon,wherein the occlusion balloon is configured for inflation to partiallyocclude the lumen when in an inflated state and further configured fordeflation or removal after a period of time

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a cannula within a vessel wall in which at a distal end, anexternal expandable balloon anchors the cannula in the coronary vein,while an internal balloon provides the necessary obstruction to cause adrop in pressure according to an exemplary embodiment of the presentdisclosure, wherein further impedance electrodes are placed distally tolocally size the coronary sinus while additional electrodes are placedinternal to the balloon for sufficient inflation and hence occlusion ofthe vein according to the distal size measurement;

FIG. 2A shows a detailed version of a cannula's multi-lumen catheterwith inner and outer balloons according to an exemplary embodiment ofthe present disclosure;

FIG. 2B shows cross-sectional views of exemplary embodiments of multiplelumens within a cannula according to exemplary embodiments of thepresent disclosure;

FIG. 3A shows a cannula inserted into the coronary sinus via theaxillary vein according to an exemplary embodiment of the presentdisclosure;

FIG. 3B shows an embodiment of a cannula containing a resorbablestenosis according to an exemplary embodiment of the present disclosure;

FIG. 4A shows a minimally invasive surgical insertion of aretroperfusion cannula with direct puncture of the axillary vein andcatheterization into the coronary sinus according to an exemplaryembodiment of the present disclosure;

FIG. 4B shows the cannula of FIG. 4A after the graft is fixed inposition at the coronary sinus;

FIG. 4C shows the cannula of FIG. 4A as the axillary artery is preparedand the proximal side of the graft is anastomosed to the axillaryartery;

FIG. 5 shows the implantation of the auto-retroperfusion cannulae in theaxillary and femoral regions;

FIG. 6 shows a distribution of selective perfusion territories whereinZone 1 corresponds to retroperfusion at the level of LADinterventricular anterior vein, which corresponds to the anterior andlateral wall of the left ventricle, and wherein Zone 2 is at the levelof the obtuse marginal circumflex vein, and Zone 3 is at the level ofthe posterolateral circumflex vein; and

FIG. 7 shows a block diagram of a regional hypothermia system and kitused in connection with an exemplary device or system of the presentdisclosure.

DETAILED DESCRIPTION

The present disclosure describes a cannula for acute and chronicretroperfusion that is designed for percutaneous insertion into thecoronary sinus and proximally connecting to the subclavian artery. Thisallows retroperfusion of oxygenated blood through the coronary venoussystem to decrease an acute ischemic area during an acute myocardialinfarction event.

An exemplary embodiment of the disclosure, illustrated in FIG. 1, showsa cannula 100 within a vessel wall 140, with the proximal portion (notshown) being a graft. The distal portion of the cannula includes acatheter 101 with an expandable external balloon 121. The catheter maybe made of any appropriate material used in the art, such aspolyurethane, silicone rubber, or other appropriate polymeric material.The distal end may also contain pressure sensors 124 for monitoringpurposes and impedance electrodes 123 for measuring the vessel andsizing the external balloon 121 accordingly.

The external expandable balloon 121 anchors the cannula in the coronaryvein. Additionally, the external balloon prevents backflow of bloodleaving the cannula. In this embodiment, a second, internal balloon 122serves to provide the pressure drop required for gradual arterializationof the vein. The balloons may be made of any material suitable for theirfunction, including but not limited to, polyethylene, latex,polyestherurethane, or combinations thereof. The balloons may beconnected to secondary lumens within the cannula, which are, in oneembodiment, connected to percutaneous ports emerging from the proximalend of the cannula. The percutaneous ports may be used to inflate ordeflate the balloons during retroperfusion. In one exemplary embodiment,the internal balloon 122 may be removed completely via the secondarylumen when vein arterialization is complete. As in the embodimentillustrated in FIG. 1, an external balloon and an internal balloon maybe concentric to each other. In other embodiments, the internal andexternal balloons may be located on distinct portions of the cannula.

Some exemplary embodiments may contain two tetrapolar sets of electrodes123 to measure the vessel near the distal tip 120 of catheter and tosize the balloon accordingly. The selective region of the coronary sinuscan be sized using these excitation and detection electrodes asdescribed in more detail within the pending patent application, “Systemand Method for Measuring Cross-Sectional Areas and Pressure Gradients inLuminal Organs,” U.S. patent application Ser. No. 10/782,149, filed onFeb. 19, 2004, which is incorporated by reference herein in itsentirety. In that application, a description is provided of aconductance catheter that is used to determine size of blood vessels.

In embodiments of the cannula that do not include impedance electrodes,the sizing of the exterior balloon may also be accomplished based on thecompliance of the balloon measured ex vivo and in vivo. This methodrequires the calibration of the balloon volume and hence diameter invitro subsequent to in vivo. This alternative method avoids the need forelectrodes and impedance sizing but may be less accurate.

Once the lumen size of the applicable region of the coronary sinus isdetermined, the balloon is expanded accordingly. It is recalled that avein is rather compliant at lower pressures and hence an appropriatediameter is selected to maintain the cannula lodged into the lumen. Foracute applications, saline may be used to fill the balloon. For longerterm applications, gels or silicones may be used to fill the balloon.

FIG. 2A shows the distal portion of the cannula 200 within the vesselwall 240. The body of the cannula houses two or more lumens with avariety of possible configurations, some of which are shown in FIG. 2B.In the embodiment illustrated, the cannula contains a primary lumen 203and multiple secondary lumens 204. The secondary lumens may connect toan expandable exterior balloon 221 and/or interior balloon 222. Thesecondary lumen may also contain pressure sensors that allow internalmonitoring of the cannula during retroperfusion.

The primary lumen 203 is the conduit that allows the oxygenated bloodflow derived from an artery to flow into the coronary sinus. The lumenof the catheter is designed to provide an optimal stenosis geometry forthe desired initial pressure drop and to ensure undisturbed flow in thecoronary venous system. In various embodiments, the secondary lumens 204may be used for a variety of different purposes, such as inflation,deflation, and removal of interior and exterior balloons, coronary sinuspressure measurement, cannula pressure measurement, and drug delivery.In one exemplary embodiment, the secondary lumens 204 are operativelycoupled with proximal extensions that branch from the graft body in suchway that they are employed as percutaneous access ports.

FIG. 3A presents a detailed illustration of an exemplary embodiment of acannula, with its proximal end being a graft 302, that contains astenosis which causes a drop in the pressure of blood passing throughthe cannula. The stenosis can be imposed by inflation of a balloon thatpartially occludes the lumen or by imposing a resorbable material withinthe lumen. A variety of materials may be used to construct theresorbable stenosis, such as, for example, polyols and magnesium alloy.The most widely used polyols are mannitol, sorbitol and maltitol.Mannitol is used in the description of the examples herein. A mold ofthe computed shape will be used to construct the stenosis usingcomputer-assisted design while the magnesium alloy geometry will besculpted by laser from a single tube. Mannitol is a naturally occurringnonreducing acyclic sugar compound widely used in foods,pharmaceuticals, medicine and chemical industries. Crystalline Mannitolexhibits a very low hygroscopicity, making it useful in products thatare stable at high humidity.

Mannitol is often added in dried protein formulations as the bulkingagent as it has the tendency to crystallize rapidly from aqueoussolutions. It has recently been shown that acetylsalicylic acid, whichis an active ingredient of aspirin, can be mixed with Mannitol withoutaffecting its properties. This is ideal as it will provideantithrombotic properties to prevent coagulation of blood during theresorption of the stenosis. Alternatively, magnesium alloys may be usedwhich are currently used in drug-eluting bioabsorbable stents. Magnesiumis a natural body component with beneficial antithrombotic,antiarrythmic and antiproliferative properties. The degradation rate ofmagnesium alloy has been shown to be linear and complete after 2-3months. The use of degradable magnesium alloys leads to electronegativeand therefore, hypothrombogenic surfaces. As an essential element,slowly degrading magnesium should not harm tissue, particularly sincemagnesium solutions up to 0.5 mol/l are well tolerated if givenparenterally. The mechanical properties and corrosion of magnesiumalloys are quite controllable under physiological conditions and matchthe requirements for degradable stenosis. The stenosis mold 330 is theninserted into the catheter portion of the cannula very close to theproximal inlet. The graft 302 may then be glued at this junction asshown in FIG. 3A.

It should be noted that the resorption rate of mannitol is a function ofmolecular weight, crystallinity, and particle size. The compound isprepared so that it will resorb in approximately 8 weeks. The magnesiumalloys have been shown to resorb within 8-12 weeks.

For balloon occlusions, the desired occlusion is obtained by measurementof pressure at the tip of the cannula during inflation of the balloon.Once the desired intermediate pressure is obtained, the balloon volumeis finalized. The patient is allowed to arterialize at the pressure forsome time. At the end of such period (typically 2-3 weeks), theocclusion is removed by deflation of the balloon. In an exemplaryembodiment, the inner lumen containing the inner balloon may beremovable and hence withdrawn.

The cannula is intended for insertion from either the axillary 341 orfemoral (not shown) veins into the coronary sinus. The proximal graft302 is anastomosed to the adjacent artery 342. The graft may be made ofany biocompatible, nonresorbable polymer with the necessary strength tosupport the surrounding tissue and withstand pressure from blood flowand the necessary flexibility to form an anastomosis with between theartery and the vein within which the cannula is housed. For example, amaterial such as GORE-TEX (polytetraflouroethylene) is suitable for usein the graft. In exemplary embodiments, the total length of the graft isapproximately 6 cm and that of the attached catheter is 8-10 cm, butthey may be of any lengths such that their dimensions allow ananastomosis between the human coronary sinus and the subclavian arteryto be made. Access ports 306 which connect to and are in fluid contactwith the secondary lumens branch off of the proximal graft 302 in someembodiments.

The diameter within the cannula will, in certain exemplary embodiments,be approximately 4 mm, but may be of any diameter such that the cannulaallows sufficient blood flow and can be accommodated by the relevantvessels. The geometry of the stenosis will be varied to ensure anapproximately 50 mm Hg pressure drop and a sufficient entrance lengthinto the coronary vein to ensure fully developed flow.

To perform automatic retroperfusion using the present cannula, theaxillary vein 441 and the axillary artery 442 are exposed as shown inFIGS. 4A-C and FIG. 5. The same procedure may be performed using thefemoral vein 543 and the femoral artery 544 as shown in FIG. 5. Thedistal end portion of the cannula 400 is then introduced into theaxillary vein 441. This may be done using the well-known Seldingertechnique, which includes passing the cannula over a guide wire underfluoroscopy. The distal end portion of the cannula is then directed (viafluoroscopy, direct vision, transesophageal echocardiogram, or othersuitable means) through the vasculature (e.g., the subclavian vein andthe superior vena cava) and into the right atrium of the heart. Thedistal end portion of the cannula is further advanced through the rightatrium and into the coronary sinus 446, which is the coronary vein. Whenthe distal end portion of the cannula reaches the desired location inthe coronary sinus, measurement of the sinus is made and the externalballoon is inflated accordingly.

Next, an anastomosis 405 of the proximal graft portion 402 of thecannula and the artery 442 may be accomplished by suturing the graftsection to the axillary artery as shown in FIG. 4C. This approach couldbe used for long term arterialization of the coronary venous system,which can replace coronary artery bypass graft.

Alternatively, the autoretroperfusion cannula can be inserted bypercutaneous puncture (under local anesthesia) in the axillary vein 541and axillary artery 542 and both ends connected through a quickconnector 545. This procedure may also be performed using the femoralvein 543 and artery 544, as shown in FIG. 5B. This procedure can be usedfor acute patients or for short periods of arterialization of thecoronary veins to stabilize the patient as a bridge to anotherprocedure.

Once the cannula is in place, normal antegrade blood flow continues asusual, but oxygenated blood will be automatically retroperfused throughthe cannula to the ischemic myocardium via the coronary sinus. Theoxygenated blood flow through the cannula occurs throughout the cardiaccycle with a pulsatile flow pattern, but with a peak flow and pressureat the end of systole and the beginning of diastole. Back-flow of bloodinto the right atrium from the coronary sinus is prevented by theballoon.

It should be noted that the aforementioned procedures can be done underlocal anesthesia. Depending on the patient's particular condition,auto-retroperfusion can last for minutes, hours, days, or months. Duringretroperfusion, the secondary lumens can be used for coronary sinuspressure measurement and the delivery of drugs, cells, genes, or growthfactors. It is expected that the access ports 406, which are fluidlyconnected with the secondary lumens, and the graft section will besubcutaneous.

As this method is based on selective retroperfusion, there is arelationship between the site of the coronary sinus where the cannula isanchored and the region of the heart requiring treatment. FIGS. 6A-6Bshow several zones of interest. Zone 1 651, shown from an anterior viewin FIG. 6A and from a posterior view in FIG. 6B, corresponds toretroperfusion at the level of the LAD interventricular anterior vein,which corresponds to the anterior and lateral wall of the leftventricle. This is the largest area of the left ventricle to be perfusedand hence clinically the most relevant. This area is the most distal tothe coronary sinus and can be determined by sizing of the vein throughthe impedance electrodes. Zone 2 652 covers the level of the obtusemarginal circumflex vein and is more proximal to the coronary sinus.Zone 3 653 covers the level of the posterolateral circumflex vein, whichis the smallest area of the left ventricle to be perfused and is themost proximal to the coronary sinus. Hence, the position of thecatheter, which can be determined by sizing of the vein throughimpedance measurements, can determine the perfusion territory. This willserve as a clinical strategy to treat patients with LAD or LCx disease.

In addition to the foregoing, and in various embodiments of devices(such as cannulas 100, 200, and 400 and/or grafts 302, for example, ofthe present disclosure, such cannulas 100, 200, and 400 and/or grafts302 may optionally comprise a regional hypothermia system 4000configured in accordance with the following. Various regionalhypothermia systems 4000 of the present disclosure, as shown incomponent block diagram of FIG. 7 and as referenced in further detailherein, are configured for use to cool (reduce the temperature of) bloodand/or other fluids within the body for targeted delivery to a locationwithin the body. Such cooling can be from, for example, at or about 0.5°C. to as much as 10° C. cooler, for example, than the native temperatureof blood within the mammalian body. In some embodiments, localized bloodcooling of greater than 10° C. may be desired and accomplished using oneor more regional hypothermia systems 4000 of the present disclosure.

In various embodiments, regional hypothermia systems 4000 are configuredfor use within a mammalian body even at tissues that are relativelydifficult to reach due to, for example, potential occlusion of one ormore coronary and/or cerebral arteries. Such regional hypothermiasystems 4000 of the present disclosure may be useful in connection withthe reduction of perfusion injuries by cooling the region of risk,whether it be at, near, or in the heart and/or brain, may be critical toreduce reperfusion injury and to decrease infarct size, for example,prior to opening an artery in the heart or brain. Retroperfusion, asreferenced generally herein, provides an ideal mechanism to deliverblood at a target location, and the use of a regional hypothermia system4000 of the present disclosure in connection with one or more cannulas100, 200, and 400 and/or grafts 302 of the present disclosure caneffectively deliver blood at a desired/targeted temperature by way ofdelivery through open veins, for example, to the region at risk, such asa heart or brain. In general, such cannulas 100, 200, and 400 and/orgrafts 302, in connection with the use of one or more regionalhypothermia systems 4000 of the present disclosure, can allowperfusion/retroperfusion of oxygenated blood, control blood perfusionpressure within a vessel, condition a blood vessel to operate underhigher blood pressure (such as arterialization of a vein), increase flowof oxygenated blood to ischemic myocardium, and/or decrease the acuteischemic area during a myocardial infarct event, all at a relativelycolder temperature than would otherwise be allowed without the use of aregional hypothermia system.

In at least one embodiment of a regional hypothermia system 4000 of thepresent disclosure, and as shown in FIG. 7, regional hypothermia system4000 comprises a heat exchanger 4002 coupled to one or more componentsof cannulas 100, 200, and 400 and/or grafts 302 of the presentdisclosure. Heat exchanger 4002, in various embodiments, is configuredto reduce the temperature of blood passing through one or morecomponents of cannulas 100, 200, and 400 and/or grafts 302, so that theblood that is ultimately delivered to the targeted area of interest,such as being at, near, or in the heart and/or brain or at or nearanother tissue or targeted blood vessel, is at a lower temperature thannormal (or without the use of a regional hypothermia system 4000). Forexample, and in at least one embodiment, regional hypothermia system4000 is used to reduce the temperature of blood delivered at, near, orin the heart and/or brain by or about 3° C. to 4° C. via the generalblood circuit created using various cannulas 100, 200, and 400 and/orgrafts 302.

Heat exchanger 4002, as referenced herein, can utilize one or morecooling products 4004, such as perfluorocarbon, liquid carbon dioxide,helium, another cooled gas, and/or another refrigerant or refrigerationmechanism known in the art, that facilitates the cooling of blood, andultimately tissues at or near the cooled blood, through components ofcannulas 100, 200, and 400 and/or grafts 302 of the present disclosure.Furthermore, one or more temperature sensors 4006 can be coupled tovarious components of cannulas 100, 200, and 400 and/or grafts 302 ofthe present disclosure, so that blood and/or tissue temperature(s)(including temperatures at, near, or in the heart and/or brain or othertissues or blood vessels, depending on the type of cannulas 100, 200,and 400 and/or grafts 302 used) can be detected by temperature sensors4006 and transmitted (via wire or wirelessly) to a remote module 270and/or another data acquisition and processing system/mechanism so thata user of regional hypothermia system 4000 can regulate localizedtemperature (at, near, or in the heart or brain or other tissues orblood vessels, for example), as desired. A generic device 4008 is shownin FIG. 7 as being operably coupled to an exemplary regional hypothermiasystem 4000 of the present disclosure, whereby generic device 4008 maycomprise one or more cannulas 100, 200, and 400 and/or grafts 302, otherdevices and/or systems of the present disclosure, and/or individualcomponents thereof. An exemplary kit 4010 of the present disclosure, asshown in the figures, comprises an exemplary regional hypothermia system4000 operably coupled to an exemplary generic device 4008 of the presentdisclosure.

Further, and in various embodiments, heat exchanger 4004 can be at thelevel of an arterial-venous connector, a double-lumen catheter, and/oranother component of one or more cannulas 100, 200, and 400 and/orgrafts 302 of the present disclosure. For the heart, this can beparticularly important for patients with a door-to-balloon time ofgreater than two hours, for patients with ST segment elevationmyocardial infarction (STEMI) that are at high risk for reperfusioninjury, and/or patients with hemodynamics instability. There are severaladvantages to using a regional hypothermia system 4000 of the presentdisclosure, including but not limited to rapid percutaneous insertionand rapid cooling of the myocardial area before opening the culpritartery to avoid the cascade of inflammatory reactions responsible forreperfusion injury.

As referenced generally above, various regional hypothermia systems 4000of the present disclosure are configured and operable to introduce mildhypothermia to reduce cardiac infarct size and general severity of thesame. Such systems 4000, in connection with various cannulas 100, 200,and 400 and/or grafts 302 of the present disclosure, can treat chronicand acute heart failure, as needed, and generally reduce the severity ofan injury and/or reduce inflammation as referenced herein, by way ofregionally reducing blood temperature.

While various embodiments of devices for controlling blood perfusionalong with regional mild hypothermia and methods of using the same havebeen described in considerable detail herein, the embodiments are merelyoffered as non-limiting examples of the disclosure described herein. Itwill therefore be understood that various changes and modifications maybe made, and equivalents may be substituted for elements thereof,without departing from the scope of the present disclosure. The presentdisclosure is not intended to be exhaustive or limiting with respect tothe content thereof.

Further, in describing representative embodiments, the presentdisclosure may have presented a method and/or a process as a particularsequence of steps. However, to the extent that the method or processdoes not rely on the particular order of steps set forth therein, themethod or process should not be limited to the particular sequence ofsteps described, as other sequences of steps may be possible. Therefore,the particular order of the steps disclosed herein should not beconstrued as limitations of the present disclosure. In addition,disclosure directed to a method and/or process should not be limited tothe performance of their steps in the order written. Such sequences maybe varied and still remain within the scope of the present disclosure.

The invention claimed is:
 1. A perfusion device, comprising: anelongated body having a lumen, a proximal end configured for placementin a first area having a first blood pressure, and a distal endconfigured for placement in a second area having a second bloodpressure; a partial occluder positioned within the lumen of theelongated body that does not fully occlude the lumen, the partialoccluder disposed within the elongated body, the partial occluderconfigured to reduce in size over time so that when the partial occluderreduces in size over time, blood flow through the lumen at the partialoccluder can increase over time, the partial occluder forming a narrowedlumen concentric with the lumen of the elongate body; wherein the lumencomprises only one opening proximal the partial occluder; and a regionalhypothermia system operably coupled thereto, the regional hypothermiasystem operable to reduce and/or regulate a temperature of a bodilyfluid flowing therethrough.
 2. The device of claim 1, wherein theregional hypothermia system is further operable to reduce and/orregulate a temperature of a portion of a mammalian body, the portionselected from the group consisting of a vessel, a tissue, and an organ.3. The device of claim 1, wherein the regional hypothermia systemcomprises a heat exchanger configured to reduce and/or regulate thetemperature of the bodily fluid.
 4. The device of claim 1, wherein oneor more components of the regional hypothermia system uses a coolingproduct to reduce and/or regulate the temperature of the bodily fluid.5. The device of claim 1, further comprising: one or more temperaturesensors coupled to the device, the one or more temperature sensorsoperable to detect the temperature of the bodily fluid.
 6. The device ofclaim 5, wherein the regional hypothermia system further comprises aremote module in wired or wireless communication with the one or moretemperature sensors, the remote module operable to and configured toreceive the detected temperature(s) and process the same to regulate,reduce, and/or increase the temperature of the bodily fluid by way ofaltering an operation of the regional hypothermia system.
 7. The deviceof claim 1, wherein the partial occluder comprises a resorbablestenosis, wherein the resorbable stenosis is configured to be resorbedover time when contacted by blood flowing through the lumen of theelongated body.
 8. The device of claim 1, wherein the partial occludercomprises: an occlusion balloon configured to deflate in size from afirst size to a second size, the second size comprising a deflated stateor the absence of occlusion of the lumen after a period of time.
 9. Thedevice of claim 1, wherein the elongated body further comprises: ananchoring balloon configured to anchor the elongated body within part ofa circulatory system.
 10. A method, comprising the steps of: introducinga distal end of an elongated tubular body of a perfusion device into ablood vessel to be conditioned, the blood vessel having a first bloodpressure therein, the perfusion device comprising: the elongated bodyhaving a lumen, a proximal end configured for placement in a first areahaving the first blood pressure, and the distal end configured forplacement in a second area having a second blood pressure, a partialoccluder positioned within the lumen of the elongated body that does notfully occlude the lumen, the partial occluder disposed within theelongated body, the partial occluder configured to reduce in size overtime so that when the partial occluder reduces in size over time, bloodflow through the lumen at the partial occluder can increase over time,the partial occluder forming a narrowed lumen concentric with the lumenof the elongate body, wherein the lumen comprises only one openingproximal the partial occluder, and a regional hypothermia systemoperably coupled thereto, the regional hypothermia system operable toreduce and/or regulate a temperature of a bodily fluid flowingtherethrough; introducing the proximal end of the elongated tubular bodyinto a second blood vessel such that blood flow is received within theinterior of the elongated tubular body, the second blood vessel having asecond blood pressure therein which is higher than the first bloodpressure; reducing and/or regulating a temperature of blood flowingthrough the elongated tubular body using the regional hypothermia systemoperably coupled to the elongated tubular body; and reducing the size ofthe stenosis over time such that the first blood pressure at the distalend of the elongated body is approximately the same as the second bloodpressure at the proximal end.
 11. The method of claim 10, wherein theelongated tubular body introduced into the blood vessel and the secondblood vessel further comprises an anchoring balloon configured to anchorthe elongated tubular body within part of a circulatory system, andwherein the method further comprises the step of: inflating theanchoring balloon to anchor the elongated tubular body within the bloodvessel or the second blood vessel.
 12. The method of claim 10, whereinthe stenosis comprises a balloon occlusion and the step of reducing theheight of the stenosis over time comprises deflating or removing theballoon occlusion positioned within the interior of the elongatedtubular body.
 13. The method of claim 10, wherein the stenosis comprisesa resorbable stenosis and the step of reducing the height of thestenosis over time comprises deflating the gradual resorption of thestenosis within the interior of the elongated tubular body.
 14. Themethod of claim 10, wherein the step of reducing and/or regulating atemperature of blood flowing through the elongated tubular body isperformed to treat a cardiac condition.
 15. A cannula, comprising: anelongated body having a lumen, a proximal end configured for placementin a first area having a first blood pressure, a distal end configuredfor placement in a second area having a second blood pressure, whereinthe first blood pressure is higher than the second blood pressure; apartial occluder positioned within the lumen of the elongated bodybetween the proximal end and the distal end and closer to the proximalend than the distal end, the partial occluder disposed within theelongated body, the partial occluder selected from the group consistingof an occluder balloon and a resorbable stenosis, the partial occluderconfigured so, at a initial height thereof, the partial occluder doesnot fully occlude the lumen of the elongated body and further configuredto gradually equalize the first blood pressure at the first area withthe second blood pressure at the second area, the partial occluderforming a narrowed lumen concentric with the lumen of the elongate body;wherein the lumen comprises only one opening proximal the partialoccluder; and a regional hypothermia system operably coupled thereto,the regional hypothermia system operable to reduce and/or regulate atemperature of a bodily fluid flowing therethrough.
 16. The cannula ofclaim 15, wherein the regional hypothermia system is further operable toreduce and/or regulate a temperature of a portion of a mammalian body,the portion selected from the group consisting of a vessel, a tissue,and an organ.
 17. The cannula of claim 15, wherein the regionalhypothermia system comprises a heat exchanger configured to reduceand/or regulate the temperature of the bodily fluid, and wherein thecannula further comprises one or more temperature sensors coupledthereto, the one or more temperature sensors operable to detect thetemperature of the bodily fluid.
 18. The cannula of claim 15, whereinthe elongated body further comprises: an anchoring balloon configured toanchor the elongated body within part of a circulatory system.
 19. Thecannula of claim 15, wherein the partial occluder comprises theresorbable stenosis, wherein the resorbable stenosis is configured to beresorbed over time when contacted by blood flowing from the proximal endto the distal end of the elongated body.
 20. The cannula of claim 15,wherein the partial occluder comprises the occlusion balloon, whereinthe occlusion balloon is configured for inflation to partially occludethe lumen when in an inflated state and further configured for deflationor removal after a period of time.